The invention relates to peptidomimetics which are substituted derivatives of 1,2,5 thiadiazolidin-3-one-1,1-dioxide.
Degenerative diseases associated with serine proteases such as human leukocyte elastase include cystic fibrosis, chronic obstructive pulmonary disease (e.g., emphysema and asthma), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, chronic bronchitis, psoriasis, rheumatoid arthritis, pancreatitis, periodontal disease, and other inflammatory diseases.
Diseases associated with cysteine proteases include cancer metastasis, osteoporosis and osteoarthritis (McGrath et al. (1997) Nature: Structural Biology 4(2):105-109), bone resorption, muscular dystrophy, parasitic diseases (leishmaniasis, malaria) (Li et al. (1996) Bioorg. Med. Chem. 4(9):1421-1427; Rosenthal et al. (1993) J. Clin. Invest. 91:1052-1056), inflammation, common cold (Webber et al. (1996) J. Med. Chem. 39:5072-5082), and hepatitis A (Malcolm et al. (1996) Biochemistry 34:8172-8179).
The invention features a compound having the formula (I) 
Each of R1 and R3, is independently selected from H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R5 is selected from the values for R1 and halo. R2 is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and Rxxi (amino acids). R4 is H, alkyl, aryl, aralkyl, an amino acid side chain, xe2x80x94PO(ORA)2, xe2x80x94Nxe2x95x90Cxe2x95x90O, xe2x80x94(NHCHRiCO)ORC, xe2x80x94NHCOORC, xe2x80x94NHCONRXRY, xe2x80x94(Cxe2x95x90O)xe2x80x94Q, xe2x80x94CH(Ri)NHW, xe2x80x94[CHRi(r)NH(Cxe2x95x90O)]rRC, xe2x80x94[CHRi(r)(Cxe2x95x90O)NH]rRC or xe2x80x94NHG. Q is xe2x80x94ORC, xe2x80x94OJ, NRYRZ, a halogen, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qORC, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qNRCRE, xe2x80x94OPn, or xe2x80x94NHPn. Pn is a polymer; each of W and W1 is H, G, or xe2x80x94(Cxe2x95x90O)NHCHRiCOORC. Each of q and r is an integer between 1 and 10. R6 is selected from H, alkyl, aryl, aralkyl, xe2x80x94Nxe2x95x90Cxe2x95x90O, xe2x80x94(Cxe2x95x90O)RB, xe2x80x94(Cxe2x95x90O)Qxe2x80x2, xe2x80x94(NHCHRxi(Cxe2x95x90O))ORD, xe2x80x94NH2, xe2x80x94NHG, xe2x80x94NHCOORD, xe2x80x94NH(Cxe2x95x90O)NRKRL, xe2x80x94O(Cxe2x95x90O)CH2xe2x80x94(OCH2CH2)2xe2x80x94OR, and xe2x80x94Oxe2x80x94X. R is alkyl. Qxe2x80x2 is xe2x80x94ORD, xe2x80x94OJ, xe2x80x94NRKRL, xe2x80x94[NHCHRxi(z)(Cxe2x95x90O)]zxe2x80x94ORD, or a halogen. X is xe2x80x94(Cxe2x95x90O)RB, xe2x80x94[(Cxe2x95x90O)CH(Rxi(z))xe2x80x94NH]zXp, xe2x80x94CH(Rxi)NHY, xe2x80x94CHRxi(NH(Cxe2x95x90O)CHRxi(p))pxe2x80x94NHW1, xe2x80x94[(Cxe2x95x90O)NHCHRxi(z)]zxe2x80x94(Cxe2x95x90O)ORD, xe2x80x94(Cxe2x95x90O)ORD, xe2x80x94S(O)nRB, or xe2x80x94N(SO2RQ)xe2x80x94[(Cxe2x95x90O)K]. Xp is H or G, G being an amino protecting group. J is a carboxyl protecting group. Y is H, RB, xe2x80x94(Cxe2x95x90O)RB, or G; z is between 1 and 10, n is from 0 to 2. K is RB, xe2x80x94ORB, xe2x80x94NHRB, xe2x80x94OCHRxiNHV, xe2x80x94[NHCHRxi(m)(Cxe2x95x90O)]mORB, or xe2x80x94[NHCHRxi(m)(Cxe2x95x90O)]mNRCRF. V is G, H, or xe2x80x94(Cxe2x95x90O)CHRxiNHZ. Z is G or H; m is from 1 to 2. In addition, R5 and R6 can be taken together to form a lactone. Each of Ri through Rxxi is independently selected from an amino acid side chain. Each of RA and RB is independently selected from alkyl, aryl, aralkyl, alkaryl, and heterocyclic radical. Each of RC and RD is independently selected from H and the values for RA. Each of RE and RF is independently selected from (heterocyclic radical) alkyl. Each of RY and RZ, and each of RK and RL, is independently selected from the values for RC. Furthermore, each pair (RY and RZ, or RK and RL) can be taken together to form a bivalent moiety selected from alkylene, heterocyclic diradical, alkenylene, arylene, or alkylarylene. RQ is selected from the values of RA and NHRr. Rr is alkyl, aryl, or aralkyl, provided that where one of R5 and R6 is H and the other is benzyl, and one of R3 and R4 is H, the other of R3 aand R4 is not alkyl; and provided that where one R3 and R4 is H, and the other is alkyl, and one of R5 and R6 is H, the other R5 and R6 is not xe2x80x94O(Cxe2x95x90O)-aryl. The invention also features oligomers and polymers containing one or more of the disclosed inhibitor compounds.
The invention also features oligomers and polymers containing one or more of the disclosed inhibitor compounds. One embodiment is a peptidomimetic composition including between 1 and 20 monomers of a compound of formula (II); and between 0 and 19 amino acid residues. The monomers and amino acid residues are linked to each other by amide linkages, and the terminal monomers or amino acid residues are terminated by hydroxyl, amino, xe2x80x94OJ, or xe2x80x94NHG to form carboxyl, primary amide, or protected amino or carboxyl groups. For example, a terminal monomer may have a HOxe2x80x94[(Cxe2x95x90O)xe2x80x94 or a H[NHxe2x80x94 terminus, where the bracket is the bracket in formula II. Formula II is shown below. 
In formula II, A4 is selected from xe2x80x94[NHCH(Ri)xe2x80x94, xe2x80x94[(Cxe2x95x90O)xe2x80x94, and xe2x80x94[NHxe2x80x94. B6 is selected from xe2x80x94CH(Ri)NH]xe2x80x94, xe2x80x94NH]xe2x80x94 and xe2x80x94(Cxe2x95x90O)]xe2x80x94. Each of R1 and R3 is independently selected from the H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R5 is selected from the values for R1 and halo. R2 is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and an amino acid side chain. G is an amino protecting group. J is a carboxyl protecting group. Each Ri is independently selected from an amino acid side chain. In some embodiments, the sum of the number of monomers and the number of amino acid residues is between 4 and 10, or between 2 and 6. In other embodiments, the number of monomer units is preferably between 2 and 8; the number of amino acid residues is 0, or between 0 and 6; at least two of the monomer units are the same; at least two of the monomer units are different; two of the monomer units have different R1 groups; or combinations thereof.
Another aspect of the invention features a method for synthesizing a peptidomimetic product. The method includes covalently linking a compound of formula I to an amino acid residue or a peptidomimetic reactant having an isocyanate, chloroformate, hydroxyl, or preferably amino, activated amino, carboxyl, or activated carboxyl functional group. The resulting linking moiety is selected from urea, urethane, ester, and preferably amide linkages.
The invention also features a method of N-chloromethylating a cyclic N-acylated sulfamide, or the sulfonamide analog, including reacting a compound of formula III: 
with at least 2 equivalents of a bisulfite adduct of formaldhyde in thionyl chloride at a temperature between 50xc2x0 C.-120xc2x0 C. for a reaction time between 2-30 hours. In formula III each of R1 and R3 is independently selected from H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R2 is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and Rxxi. R4 is H, alkyl, aryl, aralkyl, an amino acid side chain, xe2x80x94PO(ORA)2, xe2x80x94Nxe2x95x90Cxe2x95x90O, xe2x80x94(NHCHRiCO)ORC, xe2x80x94NHCOORC, xe2x80x94NHCONRXRY, xe2x80x94(Cxe2x95x90O)xe2x80x94Q, xe2x80x94CH(Ri)NHW, xe2x80x94[CHRi(r)NH(Cxe2x95x90O)]rRC, xe2x80x94[CHRi(r)(Cxe2x95x90O)NH]rRC, or xe2x80x94NHG. Q is xe2x80x94ORC, xe2x80x94OJ, xe2x80x94NRYRZ, a halogen, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qORC, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qNRCRE, xe2x80x94OPn, or xe2x80x94NHPn. Pn is a polymer, each of W and W1 is H, G, or xe2x80x94(Cxe2x95x90O)NHCHRiCOORC, and each of q and r is an integer between 1 and 10. Each of Ri through Rxxi is independently selected from an amino acid side chain. RA, RC, RE, RY and RZ are as in formula I. In some embodiments, the amount of bisulfite adduct is at least 3 equivalents, between 5 and 10 equivalents, or between 4 and 8 equivalents. In another embodiment, R4 and R6 of formula III are not selected from reactive functional groups such as carboxyl, primary and secondary amines, amino, aldehyde, and primary amides. For example, R4 is H, alkyl, aryl, aralkyl, an amino acid side chain, xe2x80x94PO(ORA)2, xe2x80x94(NHCHRiCO)ORC, xe2x80x94NHCOORC, xe2x80x94NHCONRXRY, xe2x80x94(Cxe2x95x90O)xe2x80x94Q, xe2x80x94CH(Ri)NHW, xe2x80x94[CHRi(r)NH(Cxe2x95x90O)]rRC, xe2x80x94[CHRi(r)(Cxe2x95x90O)NH]rRC, or xe2x80x94NHG, where Q is xe2x80x94ORC, xe2x80x94OJ, xe2x80x94NRYRZ, a halogen, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qORC, xe2x80x94[NHCHRi(q)(Cxe2x95x90O)]qNRCRE, xe2x80x94OPn, or xe2x80x94NHPn, provided each of RC, RX, and RY is not hydrogen.
The disclosed inhibitors are useful in methods of treating a protease-related condition, such as a degenerative disease, wherein a pharmaceutically effective amount of a composition including one or more disclosed inhibitors is administered to a patient. The invention also features synthetic chemical methods of making the disclosed compounds, including synthetic intermediates.
Other features and advantages of the invention will be apparent from the detailed description and examples below.